Project Summary: The broad goal of our research program is to understand how neural circuit function depends on the intrinsic properties of component cells and synapses. The specific goal of this proposal is to determine how synaptic inhibition in inner-retinal circuits shapes responses observed in retinal ganglion cells (GCs), the retinal output channels. This proposal is focused on inhibition in a well-studied inner-retinal circuit: the rod bipolar (RB) cell pathway of the mouse retina, which comprises two central neurons, the ON RB and the AII amacrine cell (AC). The AII distributes the RB signal to several retinal output channels, most significantly the ON ? and OFF ? and ? GCs, and in the past project period, we identified two novel ACs (nNOS-1 and Rpb4) that provide synaptic inhibition to the RB-AII network. Both of these ACs receive input from the type 6 ON cone bipolar (CB) cell, and the properties of the type 6 CB are thought to generate the contrast-sensitivity and well-characterized nonlinear receptive field of the ON ? GC. Therefore, we advance the hypothesis that local contrast in the visual scene best engages these novel inhibitory circuits and that the response properties of nNOS-1 and Rpb4 ACs should be evident in the responses of AIIs and downstream ON ? and OFF ? GCs. Our goal is to elucidate cellular properties and responses to physiological stimuli at various stages in the RB pathway to understand the functions of these novel inner retinal circuits. The two specific aims proposed will generate an understanding of how variations in the visual scene modulate signal coding within individual retinal output channels: Aim 1 tests the hypothesis that nNOS-1 ACs exhibit a non-classical receptive field surround that is manifested in the responses of downstream neurons in the retinal circuit; Aim 2 expands our combined anatomical and physiological analyses to resolve how distinct inhibitory circuits converge on GCs and permit coding of unique components of the visual scene. Relevance to Public Health: Understanding how visual stimulus coding is implemented by retinal synapses informs the design of retinal prosthetics and the study of animal models of human retinal diseases. The proposed work clarifies how visual signal processing is modulated at three stages in the retinal network and addresses two goals of the Retinal Diseases Program in the National Plan for Eye and Vision Research: one, it builds on knowledge gained from retinal neuroscience to understand how retinal networks process visual images, and two, it works toward identifying the post photoreceptor neural components of adaptation.